Synthesis of 4-aminopyrido[3,2-b]indole derivatives

Article abstract of DOI:10.1007/s11172-006-0407-8

3-Arylamino-2-formylindoles were converted into oximes and then acetylated to give the corresponding O-acetyl derivatives. Chloroacetylation of the latter was accompanied by elimination of acetic acid, yielding 3-(N-aryl-N- chloroacetyl)amino-2-cyanoindol

Full text of DOI:10.1007/s11172-006-0407-8

Russian Chemical Bulletin, International Edition, Vol. 55, No. 7, pp. 1248—1254, July, 2006
1248
Synthesis of 4ꢀaminopyrido[3,2ꢀb]indole derivatives
S. Yu. Ryabova, L. M. Alekseeva, E. A. Lisitsa, and V. G. Granikꢀ
State Scientific Center for Antibiotics,
3a ul. Nagatinskaya, 117003 Moscow, Russian Federation.
Fax: +7 (495) 231 4284. Eꢀmail: vggranik@mail.ru
3ꢀArylaminoꢀ2ꢀformylindoles were converted into oximes and then acetylated to give the
corresponding Oꢀacetyl derivatives. Chloroacetylation of the latter was accompanied by elimiꢀ
nation of acetic acid, yielding 3ꢀ(NꢀarylꢀNꢀchloroacetyl)aminoꢀ2ꢀcyanoindoles. When heated
in pyridine, these nitriles underwent cyclization into novel δꢀcarboline derivatives: 4ꢀaminoꢀ1ꢀ
arylꢀ2ꢀoxoꢀ1,2ꢀdihydropyrido[3,2ꢀb]indolꢀ3ꢀyl)pyridinium chlorides. The structures of the
compounds obtained were proved by IR and 1H NMR spectroscopy and mass spectrometry.
Key words: 3ꢀarylaminoindoles, oximes, 3ꢀ(NꢀarylꢀNꢀchloroacetyl)aminoꢀ2ꢀformylindoles,
cyanoindoles, δꢀcarbolines.
There are four classes of pyridoindoles (carbolines),
δꢀcarbolines (pyrido[3,2ꢀb]indoles) being less studied than
isomeric αꢀ, βꢀ, and γꢀcarbolines. Nevertheless, some
δꢀcarboline derivatives have been found to exhibit antituꢀ
mor, antimuscarinic, antibacterial, and antiviral activiꢀ
ties.1—3 In the last decade, we developed new original
methods for the synthesis of 1ꢀarylꢀδꢀcarbolines from
3ꢀarylaminoindole derivatives.4,5 The progress in the
chemistry of 3ꢀarylaminoindoles should give rise to new
δꢀcarboline derivatives that are of synthetic, physicoꢀ
chemical, and biological interest.
A route to δꢀcarbolines we developed involves replaceꢀ
ment of the Cl atom in the side chain of 3ꢀ(NꢀarylꢀNꢀ
chloroacetyl)aminoꢀ2ꢀformylindoles by a pyridinium fragꢀ
ment or a nitro group. In reaction intermediates containꢀ
ing strong electronꢀwithdrawing substituents (pyridinium
fragment and nitro group), the acidity of the adjacent
CH2 group is increased so considerably as to promote
cyclization through this group and the 2ꢀCHO substituꢀ
ent.6,7 The present work was devoted to the synthesis of
3ꢀ(NꢀarylꢀNꢀchloroacetyl)aminoꢀ2ꢀcyanoindoles and
their cyclization with pyridine through the 2ꢀcyano group
into new, earlier inaccessible 4ꢀaminoꢀδꢀcarbolines. These
compounds could be of interest for the study of psychoꢀ
tropic activity because they contain the 4ꢀaminopyridine
fragment, which is found in such anticholinesterase drugs
as Tacrine and Amiridin.8
Nitriles are most commonly synthesized by dehydraꢀ
tion of appropriate oximes. Earlier,6,9 we have found that
3ꢀ(NꢀarylꢀNꢀchloroacetyl)aminoꢀ2ꢀformylindoles react
with hydroxylamine to give intermediate oximes, which
are transformed in situ into substituted diazepino[6,5ꢀb]inꢀ
dole 4ꢀoxides. A literature method for the synthesis of
nitriles directly from aldehydes involves hydroxylamineꢀ
Oꢀsulfonic acid. This method has been successfully emꢀ
ployed for some (both aliphatic and aromatic) aldehydes.10
However, treatment of 3ꢀ[Nꢀ(chloroacetyl)ꢀNꢀ(4ꢀnitroꢀ
phenyl)amino]ꢀ2ꢀformylindole (1a) with a double exꢀ
cess of hydroxylamineꢀOꢀsulfonic acid in methanol at
20 °C did not afford the expected nitrile 2a. Instead,
3ꢀ[Nꢀ(chloroacetyl)ꢀNꢀ(4ꢀnitrophenyl)amino]ꢀ2ꢀformylꢀ
indole dimethyl acetal (3) was obtained in 45% yield
(Scheme 1).
Nor did a reaction of 2ꢀformylꢀ3ꢀ[Nꢀ(4ꢀnitropheꢀ
nyl)amino]indole (4a) with hydroxylamineꢀOꢀsulfonic
acid yield the corresponding nitrile 5. The reaction prodꢀ
uct was 3ꢀ[Nꢀ(4ꢀnitrophenyl)amino]indoleꢀ2ꢀcarbaldeꢀ
hyde oxime (6a) (Scheme 2).
For this reason, we tried to obtain 2ꢀcyanoindoles of
the type 2a,b by transformation of 3ꢀ[(Nꢀaryl)amino]inꢀ
doleꢀ2ꢀcarbaldehyde oximes 6a,b into nitriles 5a,b folꢀ
lowed by chloroacetylation.
Oximes 6a,b were obtained in good yields by reactions
of 2ꢀdimethyliminiomethylꢀ3ꢀ[Nꢀ(4ꢀnitrophenyl)amiꢀ
no]indole chloride (7) (an intermediate in the Vilsmeier
synthesis of 2ꢀformylꢀ3ꢀ[Nꢀ(4ꢀnitrophenyl)amino]indole)
and 3ꢀarylaminoꢀ2ꢀformylindoles 4a,b with hydroxyꢀ
lamine (Scheme 3). The minor product (5.5%) in the
synthesis of oxime 6a from aldehyde 4a was earlier obꢀ
tained4 10ꢀacetylꢀ2ꢀnitroindolo[3,2ꢀb]quinoline (8) (see
Scheme 3, pathway a).
Tacrine
Amiridin
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 7, pp. 1201—1207, July, 2006.
1066ꢀ5285/06/5507ꢀ1248 © 2006 Springer Science+Business Media, Inc.

Synthesis of 4ꢀaminopyridoindole derivatives
Russ.Chem.Bull., Int.Ed., Vol. 55, No. 7, July, 2006
1249
Scheme 1
Scheme 3
Scheme 2
Reagents: (a) H2NOH, AcONa, 4a; (b) H2NOH, AcONa, 4b.
various conditions. On heating of nitrile 5 with chloroꢀ
acetyl chloride in ethyl acetate, as well as in toluene in the
presence of anhydrous Na2CO3 (i.e., under similar condiꢀ
tions for the synthesis of 3ꢀ(NꢀarylꢀNꢀchloroacetylꢀ
amino)ꢀ2ꢀformylindole 1a (see Ref. 9), the reaction did
not occur, the starting reagent being recovered. Chloroꢀ
acetylation in DMF in the presence of triethylamine at
room temperature gave 1ꢀchloroacetyl derivative 9 rather
than 3ꢀ(Nꢀchloroacetyl) derivative (2a) (Scheme 4). The
1H NMR spectrum of compound 9 shows no signals at
δ 11—12 characteristic of the proton at the indole N atom
but contains a singlet at δ 9.88 due to the proton at N(3).
This fact motivated us to carry out chloroacetylation of
2ꢀformylindole 4a in DMF in the presence of triethylꢀ
amine. In this case, earlier reported compound 1a was
obtained (see Ref. 9 and Scheme 4).
The first step in the chloroacetylation in the presence
of a base is deprotonation of 2ꢀformylꢀ (4a,b) and 2ꢀcyano
derivatives (5), which ultimately determines the regioꢀ
selectivity of the reaction.
The deprotonation of compound 4 can proceed in two
ways leading to anions A and B (Scheme 5). Anion B is
stabilized by the existence of its two resonance strucꢀ
tures, which makes it thermodynamically more favorable
1
According to H NMR data, oximes 6a,b exist as a
mixture of the synꢀ and antiꢀisomers (2 : 3). The specꢀ
tra show doubled signals for the H(4), NH, OH, and
CH protons. Oxime 6a was converted into nitrile 5 in
72% yield by heating with copper(II) acetate in acetoniꢀ
trile.11 Other dehydration procedures (heating in a mixꢀ
ture of pyridine and acetic anhydride and heating in toluꢀ
ene or DMF with MgSO4 in the presence of pꢀtoluꢀ
enesulfonic acid) failed. It should be noted that the yield
of nitrile 5 (72%) was not reproduced on a larger scale:
with increased amounts of the reagents, the yield diminꢀ
ished. Nevertheless, we obtained a sufficient amount of
compound 5 for a study of its chloroacetylation under

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Russ.Chem.Bull., Int.Ed., Vol. 55, No. 7, July, 2006
Ryabova et al.
Scheme 4
Reagents and conditions: i. ClCH2COCl, DMF, Et3N; ii. ClCH2COCl, DMF, Et3N or toluene, Na2CO3.
than anion A. For this reason, the chloroacetylation of
2ꢀformylindole 4 at the exocyclic N atom to give comꢀ
pound 1 is dominant.
In this case, the stabilizing effect on the anionic cenꢀ
ter can be exerted mainly by the cyano group. The differꢀ
ence is that this group (in contrast to the formyl one) only
slightly affects the conjugation with the reactive site
(σRꢀconstants for the CN and CHO groups are 0.08
and 0.24, respectively).12 In contrast, the inductive elecꢀ
tronꢀwithdrawing effects of the CN and CHO groups
are opposite (their σIꢀconstants are 0.56 and 0.25, reꢀ
spectively);12 in compound 5, the cyano group stabiꢀ
lizes the Nꢀendo anion mainly by the inductive mechaꢀ
nism. The above structure of anion C suggests its stability
and explains why an acylating agent attacks the indole
N atom.
Scheme 5
The target 3ꢀ(Nꢀchloroacetylamino)ꢀ2ꢀcyanoindoles
2a,b were obtained in 26 and 15% yields, respectively, by
chloroacetylation of Oꢀacetyloximes of 3ꢀ[(Nꢀaryl)amiꢀ
no]ꢀ2ꢀformylindoles 10a,b under the same conditions as
for aldehydes 4a,b (see Ref. 9). The chloroacetylation was
accompanied by elimination of acetic acid to form the
nitrile function. OꢀAcetyloximes 10a,b had been obtained
in good yields by treatment of oximes 6a,b with acetic
anhydride (Scheme 7).
A different pattern was observed in the deprotonation
of 2ꢀcyanoindole 5 (Scheme 6).
Refluxing of compounds 2a,b in pyridine gave new
pyridoindole derivatives 11a,b. Apparently, first the acꢀ
tive Cl atom in the side chain is replaced by the pyridinium
fragment to form intermediate 12, which undergoes in situ
Thorpe—Ziegler intramolecular cyclization through the
CN group and the activated methylene unit. At the same
time, 1ꢀchloroacetylꢀ2ꢀcyanoindole 9 in pyridine underꢀ
went only deacylation even at room temperature to give
1ꢀunsubstituted 2ꢀcyanoindole 5. Because of this, posꢀ
sible product 13 of the Thorpe—Ziegler cyclization was
not obtained (see Scheme 7).
Scheme 6
Thus, we discovered a route to previously inaccessible
4ꢀaminopyrido[3,2ꢀb]indoles, which can be of interest
for the synthesis of functionalized aminopyrido[3,2ꢀb]inꢀ
doles and for pharmacological investigations.

Synthesis of 4ꢀaminopyridoindole derivatives
Russ.Chem.Bull., Int.Ed., Vol. 55, No. 7, July, 2006
1251
Scheme 7
3ꢀ[Nꢀ(Chloroacetyl)ꢀNꢀ(4ꢀnitrophenyl)amino]ꢀ2ꢀcyanoindole
(2a). Anhydrous Na2CO3 (0.21 g, 2 mmol) and chloroacetyl
chloride (0.16 mL, 2 mmol) were added to a suspension of
Oꢀacetyloxime 10a (0.34 g, 1 mmol) in toluene (35 mL). The
reaction mixture was stirred at 80 °C for 3.5 h and left at 20 °C
for 16 h. The inorganic precipitate was filtered off. The mother
liquor was clarified by heating with activated charcoal, concenꢀ
trated by three quarters of the initial volume, and cooled. The
precipitate that formed was filtered off, washed with toluene,
and dried to give compound 2a (0.09 g). 1H NMR (DMSOꢀd6),
δ: 4.21 (s, 2 H, COCH2Cl); 7.14, 7.32, 7.43, 7.55 (all m,
1 H each, H(4)—H(7)); 7.54, 8.14 (both m, 2 H each,
C6H4NO2); 13.00 (br.s, 1 H, N(1)H).
3ꢀ[NꢀChloroacetylꢀNꢀ(4ꢀcyanophenyl)amino]ꢀ2ꢀcyanoindole
(2b) was obtained analogously from Oꢀacetyloxime 10b (0.9 g,
2.8 mmol), anhydrous Na2CO3 (0.32 g, 3.1 mmol), and chloroꢀ
acetyl chloride (0.25 mL, 3.1 mmol) in toluene (75 mL). The
yield of compound 2b was 0.14 g. 1H NMR (DMSOꢀd6), δ: 4.31
(s, 2 H, COCH2Cl); 7.25, 7.43, 7.54, 7.67 (all m, 1 H each,
H(4)—H(7)); 7.60, 7.88 (both m, 2 H each, C6H4NO2); 13.00
(br.s, 1 H, N(1)H).
Experimental
The IR spectra (Nujol) were recorded on Perkin—Elmer 457
(compounds 6a, 8, 5, 2a, 9, and 10a) and FSMꢀ1201 instruꢀ
ments (compounds 3, 6b, 2b, 10b, and 11a,b). The mass spectra
(EI) of compounds 6a, 8, 5, 2a, 9, and 10a were recorded on a
Finnigan SSQꢀ710 mass spectrometer (direct inlet probe). The
mass spectra of compounds 3, 6b, 2b, 10b, and 11a,b were reꢀ
corded on a Waters ZQꢀ2000 mass spectrometer (ESI, direct
inlet probe). 1H NMR spectra were recorded on Bruker ACꢀ200
and Bruker ACꢀ300 spectrometers in DMSOꢀd6 according to
Bruker standard procedures. The course of the reactions was
monitored and the purity of the products was checked by TLC
on Merck 60 F254 plates. The physicochemical characteristics of
the compounds obtained are given in Tables 1 and 2.
3ꢀ[Nꢀ(Chloroacetyl)ꢀNꢀ(4ꢀnitrophenyl)amino]ꢀ2ꢀformylinꢀ
dole (1a). Triethylamine (1 mL, 6.5 mmol) was added at 20 °C
to a stirred solution of 2ꢀformylindole 4a (0.6 g, 2.1 mmol) in
DMF (8 mL). Then a solution of chloroacetyl chloride (0.56 mL,
6.5 mmol) in DMF (4 mL) was added dropwise. The reaction
mixture was kept at 20 °C for 2.5 h and poured onto ice with
water (∼50 mL). The resinous precipitate that formed was filꢀ
tered off, washed with water, and dissolved in chloroform. The
solution was clarified with activated charcoal. The solvent was
removed and the residue was recrystallized from benzene (8 mL)
with activated charcoal and dried to a constant weight. The
yield of compound 1a was 0.25 g (30%). Its physicochemical
characteristics were identical with those of the compound obꢀ
tained earlier according to a known procedure.9
3ꢀ[Nꢀ(Chloroacetyl)ꢀNꢀ(4ꢀnitrophenyl)amino]ꢀ2ꢀdimethoxyꢀ
methylindole (3). A solution of hydroxylamineꢀOꢀsulfonic acid
(0.22 g, 2 mmol) in methanol (2 mL) was added to a suspension
(cooled with ice water) of aldehyde 1a (0.36 g, 1 mmol) (see
Ref. 8) in methanol (10 mL). After 7—10 min, the resulting
solution with a promptly formed precipitate was stirred at 20 °C
for 1 h. The precipitate was filtered off and washed with methaꢀ
1
nol. The yield of acetal 3 was 0.17 g. H NMR (DMSOꢀd6), δ:

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Russ.Chem.Bull., Int.Ed., Vol. 55, No. 7, July, 2006
Ryabova et al.
Table 1. Physicochemical characteristics of the compounds obtained
Comꢀ
pound
Yield
(%)
M.p./°C
(solvent)
M
Molecular
formula
Found
Calculated
(%)
С
H
N
2a
2b
3
26
15
45
72
206—208
(PriOH)
212—215
(PriOH)
218
(MeOH)
354
334
403
278
296
C
C
C
17H11N4O3Cl
18H11N4OCl
19H18N3O5Cl
57.35
57.56
64.56
64.58
56.74
56.51
64.55
64.74
60.81
60.81
3.22
3.13
3.55
3.31
4.56
4.49
3.64
3.62
4.10
4.08
15.55
15.79
16.62
16.74
10.39
10.41
20.02
20.14
18.96
18.91
5
271 decomp.
(EtOH)
248—250 decomp.
(MeCN)
C15H10N4O2
15H12N4O3
6a
95 (A)
93 (B)
87 (C)
92
C
6b
185
(50% EtOH)
240
(MeOH—Me2O)
175 decomp.
(MeCN)
155—158
(МеCN)
>360
276
354
338
318
433
413
C16H12N4O
69.82
69.55
57.27
57.56
60.31
60.35
67.69
67.91
58.41
58.48
65.11
65.35
4.65
4.38
2.99
3.13
4.36
4.17
4.42
4.43
4.09
4.02
4.30
4.05
19.79
20.28
15.82
15.79
16.85
16.56
17.47
17.60
15.53
15.50
16.56
16.57
9
72
70
77
89
81
C17H11N4O3Cl
C17H14N4O4
10a
10b
11a
11b
C
18H14N4O2
C22H16N5O3Cl•
•H2O
C23H16N5OCl•
•0.5H2O
(MeOH)
>360
(MeOH)
Table 2. MS data and IR spectra of the compounds obtained
Comꢀ
pound
MS, m/z (Irel (%))
IR (νmax/cm–1
)
2a
354 [M]+ (24), 278 [M – COCH2Cl]+ (100), 248 [M – COCH2Cl – NO]+ (37),
205 [M – COCH2Cl – HCN]+ (68)
3410, 3238 (NH), 2226 (CN),
1698 (CO)
3254 (NH), 2227 (CN), 1689 (CO),
3300 (NH), 1760 (CO)
3691 (NH), 2226 (CN)
2b
3
5
357 [M + Na]+, 691 [2 M + Na]+, 1025 [3 M + Na]+
426 [M + Na]+, 829 [2 M + Na]
278 [M]+ (100), 248 [M – NO]+ (85), 231 [M – HNO2]+ (58),
205 [M – NO2 – HCN]+ (42)
6a
296 [M]+ (83), 278 [M – H2O]+ (100), 248 [M – H2O – NO]+ (17),
233 [M – HNO3]+ (80), 218 [M – O – HCO – NO2]+ (77),
218 [M – H2O – 2 NO]+ (27)
3389, 3358 (NH, OH)
6b
9
575 [2 M + Na]+, 851 [3 M – Na]+
3329 (NH, OH), 2225 (CN)
3367, 3352 (NH), 2204 (CN),
1716, 1697 (CO)
354 [M]+ (52), 278 [M – COCH2Cl]+ (100), 248 [M – COCH2Cl – NO]+ (77),
232 [M – COCH2Cl – NO2]+ (70), 231 [M – C6H4NO2]+ (76],
205 [M – COCH2Cl – HCN]+ (57)
10a
296 [M – АсОН]+ (100), 248 [M – АсОН – NO]+ (31),
232 [M – AcOH – NO2]+ (54), 231 [M – AcOH – HNO2]+ (60),
205 [M – AcOH – NO2 – HCN]+ (50)
3309 (NH), 1745 (CO)
10b
11a
11b
341 [M + Na]+, 659 [2 M + Na]+
3344, 3294 (NH), 2214 (CN),
1757 (CO)
3526, 3344, 3304, 3117, 3651
(NH, NH2), 1629 (CO)
3554, 3340, 3304, 3117 (NH, NH2),
2233 (CN), 1658, 1631 (CO)
398 [M – Cl], 352 [M – Cl – NO2]
378 [M – Cl], 755 [2 M – 2 Cl + H]

Synthesis of 4ꢀaminopyridoindole derivatives
Russ.Chem.Bull., Int.Ed., Vol. 55, No. 7, July, 2006
1253
3.19, 3.30 (both s, 3 H each, (OMe)2); 4.22 (AB system, 2 H,
COCH2Cl); 5.70 (s, 1H, CH); 7.10, 7.22 (both m, 1 H each,
H(4)—H(7)); 7.45 (m, 2 H, H(4)—H(7)); 7.57, 8.19 (both m,
2 H each, C6H4NO2), 11.76 (br.s, 1 H, N(1)H).
charcoal and evaporated to dryness. The residue was triturated
with water. The resulting precipitate was filtered off, washed
with water, and dried. The yield of oxime 6b as a mixture of the
synꢀ and antiꢀisomers (2 : 3) was 1.01 g. A sample for analysis
was recrystallized from 50% ethanol and purified on SiO2
with chloroform as an eluent. 1H NMR (DMSOꢀd6), δ: 6.68,
7.47 (both m, 2 H each, C6H4NO2); 6.99 (1 H), 7.20 (2 H),
7.40 (1 H), 7.62 (1 H) (all m, H(4)—H(7)); 7.43 and 8.05
(both s, 1 H each, CH); 8.43 and 8.52 (both br.s, 1 H each,
C(3)NH); 11.24 and 11.83 (both s, 1 H each, OH); 11.24 (br.s,
1 H, N(1)H).
2ꢀCyanoꢀ3ꢀ[Nꢀ(4ꢀnitrophenyl)amino]indole (5). A mixture of
oxime 6a (0.3 g, 1 mmol) and cupric acetate (0.2 g, 1 mmol) was
refluxed in acetonitrile (15 mL) for 1 h and then evaporated
to dryness. After 5% H2SO4 (25 mL) was added, the mixture
was stirred and the precipitate was filtered off, washed with
water, and mixed with acetone (20 mL). The undissolved black
precipitate was filtered off. The mother liquor in acetone was
clarified with activated charcoal and concentrated to give
2ꢀcyanoindole 5 (0.2 g). 1H NMR (DMSOꢀd6), δ: 6.82, 8.02
(both m, 2 H each, C6H4NO2); 7.08 (1 H), 7.25 (3 H) (both m,
1ꢀChloroacetylꢀ2ꢀcyanoꢀ3ꢀ[Nꢀ(4ꢀnitrophenyl)amino]indole
(9). Triethylamine (0.2 mL, 1.3 mmol) was added at 20 °C to a
stirred solution of 2ꢀcyanoindole 5 (0.12 g, 0.43 mmol) in DMF
(1.5 mL). Then a solution of chloroacetyl chloride (0.11 mL,
1.3 mmol) in DMF (1 mL) was added dropwise. After 0.5 h, the
mixture was poured onto ice with water (∼10 mL). The precipiꢀ
tate that formed was filtered off and washed with water, methaꢀ
H(4)—H(7)); 9.27 (br.s,
1 H, N(1)H).
1 H, C(3)NH); 12.13 (br.s,
2ꢀHydroxyiminomethylꢀ3ꢀ[Nꢀ(4ꢀnitrophenyl)amino]indole
(6a). Procedure A. HydroxylamineꢀOꢀsulfonic acid (0.12 g,
1 mmol) in methanol (1 mL) was added to a suspension of
aldehyde 4a (0.14 g, 0.5 mmol) (see Ref. 4) in methanol (5 mL).
The reaction mixture was stirred at 20 °C for 15 min, refluxed
for 0.5 h, cooled, and concentrated. The residue was triturated
with water and the resulting precipitate was filtered off, washed
with water, and dried. The yield of oxime 6a as a mixture of the
synꢀ and antiꢀisomers (2 : 3) was 0.14 g (95%). 1H NMR
(DMSOꢀd6), δ: 6.68, 8.03 (both m, 2 H each, C6H4NO2);
7.01 (1 H), 7.20 (2 H), 7.42 (1 H), 7.63 (1 H) (all m,
H(4)—H(7)); 7.45 and 8.06 (s, 1 H, CH); 8.99 and 9.07 (br.s,
1 H, C(3)NH); 11.38 and 11.98 (s, 1 H, OH); 11.42 and 11.43
(br.s, 1 H, N(1)H).
B. Hydroxylamine hydrochloride (0.2 g, 3 mmol) and melted
sodium acetate (0.5 g, 6 mmol) were added to a suspension of
immonium salt 7 (0.69 g, 2.0 mmol) (see Ref. 4) in isopropyl
alcohol (20 mL). The reaction mixture was stirred under reflux
for 0.5 h and cooled. The inorganic precipitate was filtered off,
the filtrate was concentrated to dryness, and the residue was
triturated with water. The resulting precipitate was filtered off,
washed with water, and dried. The yield of oxime 6a was 0.55 g.
Its mixture with the oxime 6a obtained according to procedure A
did not depress the melting point.
1
nol, and ether. The yield of compound 9 was 0.11 g. H NMR
(DMSOꢀd6), δ: 5.20 (s, 2 H, COCH2Cl); 7.13, 8.16 (both m,
2 H each, C6H4NO2); 7.45, 7.67, 7.70, 8.22 (all m, 1 H each,
H(4)—H(7)); 9.88 (br.s, 1 H, C(3)NH).
2ꢀAcetoxyiminomethylꢀ3ꢀ[Nꢀ(4ꢀnitrophenyl)amino]indole
(10a). A mixture of oxime 6a (0.2 g, 0.68 mmol) and acetic
anhydride (1.5 mL) was kept at 20 °C for 16 h. The precipitate
that formed was filtered off and washed with acetic anhydride
and ether. The yield of Oꢀacetyloxime 10a was 0.16 g. 1H NMR
(DMSOꢀd6), δ: 2.19 (s, 3 H, OCOCH3); 6.76, 8.05 (both m,
2 H each, C6H4NO2); 7.06 (1 H), 7.28 (2 H), 7.49 (1 H) (all m,
H(4)—H(7)); 8.55 (s, 1 H, CH); 9.10 (br.s, 1 H, C(3)NH);
11.80 (br.s, 1 H, N(1)H).
2ꢀAcetoxyiminomethylꢀ3ꢀ[Nꢀ(4ꢀcyanophenyl)amino]indole
(10b). A mixture of oxime 6b (1.01 g, 3.6 mmol) and acetic
anhydride (5 mL) was stirred at 20 °C for 2 h. The precipitate
that formed was filtered off and washed with acetic anhydride
1
and ether. The yield of Oꢀacetyloxime 10b was 0.9 g. H NMR
(DMSOꢀd6), δ: 2.18 (s, 3 H, OCOCH3); 6.74, 7.43 (both m,
2 H each, C6H4CN); 6.98 (1 H), 7.23 (2 H), 7.46 (1 H) (all m,
H(4)—H(7); 8.49 (s, 1 H, CH); 8.59 (br.s, 1 H, C(3)NH); 11.63
(br.s, 1 H, N(1)H).
C. Hydroxylamine hydrochloride (0.2 g, 3 mmol) and melted
sodium acetate (0.25 g, 3 mmol) were added to a suspension of
aldehyde 4a (0.5 g, 1.8 mmol) in isopropyl alcohol (20 mL). The
reaction mixture was stirred under reflux for 0.5 h and cooled.
The precipitate was filtered off, washed with isopropyl alcoꢀ
hol and water, and dried to give 10ꢀacetylꢀ2ꢀnitroindoꢀ
lo[3,2ꢀb]quinoline (8) (0.03 g, 5.5%), m.p. 263.5—264 °C (cf.
Ref. 4: m.p. 263.5—264 °C). Its spectroscopic characteristics
agree with those reported earlier.4 The mother liquor was evapoꢀ
rated to dryness and the residue was triturated with water. The
resulting precipitate was filtered off, washed with water, and
dried. The yield of oxime 6a was 0.47 g. Its mixture with the
oxime 6a obtained according to procedure A did not depress the
melting point.
3ꢀ[Nꢀ(4ꢀCyanophenyl)amino]ꢀ2ꢀhydroxyiminomethylindole
(6b). Hydroxylamine hydrochloride (0.46 g, 6.6 mmol) and
melted sodium acetate (0.54 g, 6.6 mmol) were added to a susꢀ
pension of aldehyde 4b (1.04 g, 4 mmol) (see Ref. 8) in isoproꢀ
pyl alcohol (45 mL). The reaction mixture was refluxed with
stirring for 0.5 h and cooled. The inorganic precipitate was
filtered off. The mother liquor was clarified with activated
1ꢀ[4ꢀAminoꢀ1ꢀ(4ꢀnitrophenyl)ꢀ2ꢀoxoꢀ1,2ꢀdihydropyriꢀ
do[3,2ꢀb]indolꢀ3ꢀyl]pyridinium chloride (11a). A mixture of
3ꢀ[Nꢀ(chloroacetyl)ꢀNꢀ(4ꢀnitrophenyl)amino]ꢀ2ꢀcyanoindole
(2a) (0.22 g, 0.62 mmol) and pyridine (2 mL) was heated with
stirring to boiling. The resulting solution gave rise to a new
yellow precipitate. The reaction mixture was refluxed for 0.5 h
and cooled. The precipitate was filtered off and washed with
pyridine and ether. The yield of compound 11a was 0.24 g.
1H NMR (DMSOꢀd6), δ: 6.26, 6.87, 7.32, 7.55 (all m, 1 H each,
H(9)—H(6)); 7.79, 8.48 (both m, 2 H each, C6H4NO2); 7.85
(br.s, 2 H, C(4)NH2); 8.31 (2 H), 8.76 (1 H), 9.11 (2 H) (all m,
H(2´)—H(6´)); 12.79 (br.s, 1 H, N(5)H).
1ꢀ[4ꢀAminoꢀ1ꢀ(4ꢀcyanophenyl)ꢀ2ꢀoxoꢀ1,2ꢀdihydropyriꢀ
do[3,2ꢀb]indolꢀ3ꢀyl]pyridinium chloride (11b) was obtained
analogously from 3ꢀ[NꢀchloroacetylꢀNꢀ(4ꢀcyanophenyl)amino]ꢀ
2ꢀcyanoindole (2b) (0.14 g, 0.4 mmol) and pyridine (2 mL). The
yield of compound 11b was 0.14 g. 1H NMR (DMSOꢀd6), δ:
6.15, 6.89, 7.32, 7.56 (all m, 1 H each, H(9)—H(6)); 7.71, 8.13
(both m, 2 H each, C6H4CN); 7.77 (br.s, 2 H, C(4)NH2); 8.32
(2 H), 8.76 (1 H), 9.11 (2 H) (all m, H(2´)—H(6´)); 12.52 (br.s,
1 H, N(5)H).

1254
Russ.Chem.Bull., Int.Ed., Vol. 55, No. 7, July, 2006
Ryabova et al.
6. N. A. Lantsetti, S. Yu. Ryabova, L. M. Alekseeva, A. S.
Shashkov, and V. G. Granik, Izv. Akad. Nauk, Ser. Khim.,
2002, 470 [Russ. Chem. Bull., Int. Ed., 2002, 51, 506].
7. N. A. Rastorgueva, S. Yu. Ryabova, E. A. Lisitsa, L. M.
Alekseeva, and V. G. Granik, Izv. Akad. Nauk, Ser. Khim.,
2003, 2036 [Russ. Chem. Bull., Int. Ed., 2003, 52, 2149].
8. J. G. Cannon, Pharmacology for Chemists, Oxford University
Press, New York—Oxford, 1999, 272 pp.
9. S. Yu. Ryabova, N. A. Rastorgueva, E. A. Lisitsa, L. M.
Alekseeva, and V. G. Granik, Izv. Akad. Nauk, Ser. Khim.,
2003, 1312 [Russ. Chem. Bull., Int. Ed., 2003, 52, 1386].
10. C. Fizet and J. Streith, Tetrahedron Lett., 1974, 36, 3187.
11. O. Attanasi, P. Palma, and F. SerraꢀZanetti, Synthesis,
1983, 741.
This work was financially supported by the Federal
Agency on Science and Innovation (Contract No. 1/05).
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Received April 28, 2006;
in revised form May 31, 2006